br Summary br Conflict of interest br

Summary
Conflict of interest
Acknowledgments This study was supported by Grant No. 2014/13/B/NZ7/02277 from the National Science Centre, Poland.
Introduction Progesterone (P) is an anticonvulsant hormone (Backstrom et al., 1984, Herzog, 1995, Herzog, 1999, Frye et al., 2000, Reddy, 2002, Reddy, 2004) which plays an important role in women with catamenial epilepsy, a menstrual cycle-related seizure disorder (Reddy, 2016). Low P levels during the perimenstrual and ovulatory period are linked to higher seizures compared to luteal phase with high P levels (Herzog et al., 1997, Reddy, 2016). P modulates seizure susceptibility by binding to the genomic progesterone receptors (PR) and non-genomic targets by converting into allopregnanolone (AP) and related neurosteroids, which are positive modulators of GABA-A receptors (Reddy et al., 2010, Reddy, 2013, Wu et al., 2013, Carver et al., 2014, Reddy and Mohan, 2011). Consequently, P and neurosteroids play a significant role in the pathophysiology of epilepsy, anxiety, stress, and postpartum depression (Purdy et al., 1991, Smith et al., 1998a, Reddy, 2010, Reddy, 2013, Shen et al., 2010, Carver and Reddy, 2013). P and neurosteroids may exert disease-modifying effects on epileptogenesis (Reddy et al., 2010, Reddy and Mohan, 2011). Therefore, there is emergent interest in the translational potential of neurosteroid regulation of GABA-A receptors in the brain. Neuronal GABA-A receptors are composed of five subunits from several classes (α1–6, β1–4, γ1–3, δ, ε, θ, ρ1–3) (Korpi et al., 2002). The major pentameric forms include 2α, 2β, and 1γ or δ subunits. The subunit expression of these receptors varies with development stage, neuronal cell type, and blasticidin region. Such heterogeneity in receptor composition confers distinct physiological and pharmacological properties, including different roles for synaptic and extrasynaptic GABA-A receptors. Neurosteroids modulate most receptor isoforms (Belelli et al., 2002, Carver and Reddy, 2013, Carver and Reddy, 2016). They can modulate both synaptic (γ2-containing) and extrasynaptic (δ-containing) receptor isoforms (Carver and Reddy, 2013, Reddy and Estes, 2016). Neurosteroids have been shown to play a critical role in the pathogenesis of catamenial epilepsy and post-partum depression (Reddy et al., 2001, Reddy, 2013, Maguire and Mody, 2008). Alterations in the subunit expression and function of GABA-A receptors in the hippocampus have been reported during estrous cycle, pregnancy, and after delivery (Smith et al., 1998a, Smith et al., 1998b, Follesa et al., 2000, Biggio et al., 2001, Pierson et al., 2005, Gangisetty and Reddy, 2010, Wu et al., 2013, Carver et al., 2014). We have discovered that neurosteroids regulate the expression of α4 and δ-subunit plasticity in catamenial epilepsy models (Gangisetty and Reddy, 2010, Wu et al., 2013, Carver et al., 2014, Reddy, 2016). Although α1 and α2-subunits are highly expressed in limbic regions, where they mediate phasic inhibition, there is limited information on the contribution of α2-containing receptors. GABA-A receptor α2 knockout mice displayed anxiety/depression-like effects (Fritschy and Mohler, 1995, Low et al., 2000, Vollenweider et al., 2011, Durkin et al., 2011), which underscores the integral physiological role of the subunit in the brain. In human temporal lobe epilepsy, prominent upregulation of mainly the α2-subunit was seen on somata and apical dendrites, with reduced labeling on basal dendrites in hippocampal granule cells (Loup et al., 2000). However, the neuroendocrine mechanisms underlying α2-subunit plasticity in the hippocampus remain unclear.
Results
Discussion The principal outcome of this study shows that cyclical elevations in P levels during the diestrus phase and neurosteroid exposure are accompanied by subfield-specific, increased α2-subunit GABA-A receptor mRNA expression in the hippocampus. The α2-subunit GABA-A receptor contributes to phasic inhibition in the hippocampus and thereby plays a contributory role, especially in response to changes in P levels in the female brain. We have reported similar outcomes on the α4 and δ-subunits, which contribute to tonic inhibition in the brain (Gangisetty and Reddy, 2010, Wu et al., 2013, Carver et al., 2014). The α2-subunit is known to play a physiological role in cellular and behavioral responses to neurosteroids (Durkin et al., 2011). Collectively, these novel findings provide further evidence for the dynamic neurosteroid-mediated regulation of neuronal excitability with therapeutic implications in menstrual conditions such as catamenial epilepsy, premenstrual syndrome, menstrual migraine, and post-partum depression.